Reversal of morphine-induced cell-type–specific synaptic plasticity in the nucleus accumbens shell blocks reinstatement

Abstract

Drug-evoked plasticity at excitatory synapses on medium spiny neurons (MSNs) of the nucleus accumbens (NAc) drives behavioral adaptations in addiction. MSNs expressing dopamine D1 (D1R-MSN) vs. D2 receptors (D2R-MSN) can exert antagonistic effects in drugrelated behaviors, and display distinct alterations in glutamate signaling following repeated exposure to psychostimulants; however, little is known of cell-type-specific plasticity induced by opiates. Here, we find that repeated morphine potentiates excitatory transmission and increases GluA2-lacking AMPA receptor expression in D1R-MSNs, while reducing signaling in D2-MSNs following 10-14 d of forced abstinence. In vivo reversal of this pathophysiology with optogenetic stimulation of infralimbic cortexaccumbens shell (ILC-NAc shell) inputs or treatment with the antibiotic, ceftriaxone, blocked reinstatement of morphine-evoked conditioned place preference. These findings confirm the presence of overlapping and distinct plasticity produced by classes of abused drugs within subpopulations of MSNs that may provide targetable molecular mechanisms for future pharmacotherapies.opiates | nucleus accumbens | plasticity | GluA2-lacking AMPARs | ceftriaxone O pioid-based drugs are mainstays for pain management (1). However, side effects such as euphoria and the development of tolerance and dependence contribute to an increasing diversion of these readily available compounds for nontherapeutic use (2). Opioid agonist-based treatments are known to reduce some aspects of opioid addiction. On the other hand, these therapies often lead to high relapse rates when discontinued because they fail to eliminate key aspects of addiction such as conditioned associations that can trigger intense drug craving (2). Currently, development of alternative treatments for opioid addiction is hampered by a distinct lack of knowledge of the cellular plasticity that underlies persistent opioid-induced changes in behavior.The nucleus accumbens (NAc) region of the ventral striatum is involved in attribution of salience to drug-paired cues that can in turn motivate reward-related behavior (3, 4). Medium spiny neurons (MSNs), the principal cells of the NAc, are GABAergic projection neurons that receive coordinated glutamatergic afferents arising from several cortical and limbic brain regions (5, 6). MSNs are divided into two subpopulations based on expression of the dopamine receptor 1 (D1R-MSN) or dopamine receptor 2 (D2-MSN), with a small fraction (∼6-17%) expressing both receptors (7). Importantly, these subpopulations have divergent projection targets and exert antagonistic effects in rewardrelated behaviors (8).Long-lasting alterations in excitatory synaptic strength and glutamate release at MSNs produced by repeated exposure to drugs of abuse is a driving factor behind drug seeking and relapse (9-11). Numerous studies have examined effects of repeated psychostimulant exposure on synaptic strength and AMPA receptor (AMPAR)-mediated transmission in MSN subpopulations, with a majority of adaptati...

Prosapip1-Dependent Synaptic Adaptations in the Nucleus Accumbens Drive Alcohol Intake, Seeking, and Reward

“…Importantly, our data suggest that Prosapip1 controls this synaptic modifi-cation. Interestingly, exposure to cocaine and morphine triggers a switch in AMPAR subunit composition at NAc synapses (Hearing et al, 2016; McCutcheon et al, 2011). Thus, it is plausible that mTORC1 is the molecular driving force of synaptic plasticity induced by exposure to various drugs of abuse.…”

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

“…Another glutamatergic innervation to the NAc that plays a role in opioid withdrawal and aversion are those form the infralimbic cortex. Activating the infralimbic cortex projections to the NAc shell blocks morphine reinstatement and reverses the effects of morphine abstinence [97]. There is also evidence that glutamatergic projections from the VTA to the NAc may drive aversion by activating parvalbumin GABAergic interneurons, which in turn inhibit MSNs [98].…”

A NAc for Spinal Adjustments After Cocaine or Stress

“…This suggests that although cocaine and stress both tend to increase spine number or density, they ultimately lead to contrasting functional alterations, which are associated with a redistribution of synaptic strength across a population of D1-MSN spines. These opposing changes in synaptic strength after cocaine versus stress mirror some, but not all, of the psychotropic or stress-induced changes in presynaptic terminal stimulation (7,8) or more indirect synaptic or static measures of the postsynaptic surface (9). Moving forward, it can be hypothesized that this contrasting redistribution of synaptic strength on D1-MSNs after cocaine or stress is a defining characteristic underlying behavioral differences, an idea recently touched on in another paper using the same chronic social defeat stress paradigm (10).…”

“…The authors themselves are careful to point out the caveats in making such conclusions, given that published results vary based on species used, paradigm of stimuli exposure/drug administration, approaches to visualize spine dynamics or estimate synaptic strength, and length of time drug or stress free. The importance of these caveats are exemplified by data that withdrawal from cocaine (3 or 10 days) or morphine (2 weeks) can increase or decrease synaptic strength at D1-MSNs or D2-MSNs, respectively (2,7,8). …”

“…What are the biochemical or molecular mechanisms underlying the cell type–specific spinal adjustments reported here (4)? Are they distinct for the NAcSh versus other brain regions or among different experiences (7)? From a local circuit level, is there a compensatory shift between cell types and spine types?…”